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Objectives: This study aims to design and evaluate ( in silico and in vitro ) a new nicotinamide derivative as an inhibitor of VEGFR-2, a major mediator of angiogenesis Methods: The following in silico studies were performed; DFT calculations, molecular modelling, MD simulations, MM-GBSA, PLIP, and PCAT studies. The compound's in silico (ADMET) analysis was also conducted. Subsequently, the compound ((E)- N -(4-(1-(2-(4-(4-Chlorobenzamido)benzoyl)hydrazono)ethyl) phenyl)nicotinamide) was successfully synthesized and designated as compound X . In vitro , VEGFR-2 inhibition and cytotoxicity of compound X against HCT-116 and A549 cancer cell lines and normal Vero cell lines were conducted. Apoptosis induction and migration assay of HCT-116 cell lines after treatment with compound X were also evaluated., Results: DFT calculations assigned stability and reactivity of compound X . Molecular docking and MD simulations indicated its excellent binding against VEGFR-2. Furthermore, MM-GBSA analysis, PLIP experiments, and PCAT studies confirmed compound X 's correct binding with optimal dynamics and energy. ADMET analysis expressed its general likeness and safety. The in vitro assays demonstrated that compound X effectively inhibited VEGFR-2, with an IC 50 value of 0.319 ± 0.013 μM and displayed cytotoxicity against HCT-116 and A549 cancer cell lines, with IC 50 values of 57.93 and 78.82 μM, respectively. Importantly, compound X exhibited minimal toxicity towards the non-cancerous Vero cell lines, (IC 50 = 164.12 μM). Additionally, compound X significantly induced apoptosis of HCT-116 cell lines and inhibited their potential to migrate and heal., Conclusion: In summary, the presented study has identified compound X as a promising candidate for the development of a novel apoptotic lead anticancer drug., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

A new series of pyrido[2,3-d]pyrimidin-4(3H)-one derivatives having the essential pharmacophoric features of EGFR inhibitors has been designed and synthesised. Cell viability screening was performed for these compounds against A-549, PC-3, HCT-116, and MCF-7 cell lines at a dose of 100 μM. The highest active derivatives ( 8a, 8 b, 8d, 9a, and 12b ) were selected for IC 50 screening. Compounds 8a, 8 b, and 9a showed the highest cytotoxic activities and were further investigated for wild EGFR WT and mutant EGFR T790M inhibitory activities. Compound 8a showed the highest inhibitory activities against EGFR WT and EGFR T790M with IC 50 values of 0.099 and 0.123 µM, respectively. In addition, it arrested the cell cycle at pre-G1 phase and induced a significant apoptotic effect in PC-3 cells. Furthermore, compound 8a induced a 5.3-fold increase in the level of caspase-3 in PC-3 cells. Finally, docking studies were carried out to examine the binding mode of the synthesised compounds against both EGFR WT and EGFR T790M .

New 1 H -pyrazolo[3,4-d]pyrimidine derivatives were designed and synthesised to act as epidermal growth factor receptor inhibitors (EGFRIs). The synthesised derivatives were assessed for their in vitro anti-proliferative activities against A549 and HCT-116 cancer cells. Compounds 8, 10, 12a, and 12b showed potent anti-proliferative activities. Compound 12b was the most promising member with IC 50 values of 8.21 and 19.56 µM against A549 and HCT-116, respectively. Compounds 8, 10, 12a, and 12b were evaluated for their kinase inhibitory activities against wild EGFR (EGFR WT ). Compound 12b was the most potent member showing an IC 50 value of 0.016 µM. In addition, compound 12b showed noticeable activity against mutant EGFR (EGFR T790M ) (IC 50 = 0.236 µM). Flow cytometric analyses revealed that compound 12b is a good apoptotic inducer and can arrest the cell cycle at S and G2/M phases. Furthermore, it produced an 8.8-fold increase in BAX/Bcl-2 ratio. Molecular docking studies were carried out against EGFR WT and EGFR T790M .

Discovering of new anticancer agents with potential activity against tubulin polymerisation is still a promising approach. Colchicine binding site inhibitors are the most relevant anti-tubulin polymerisation agents. Thus, new quinoline derivatives have been designed and synthesised to possess the same essential pharmacophoric features of colchicine binding site inhibitors. The synthesised compounds were tested in vitro against a panel of three human cancer cell lines (HepG-2, HCT-116, and MCF-7) using colchicine as a positive control. Comparing to colchicine (IC 50  = 7.40, 9.32, and 10.41 µM against HepG-2, HCT-116, and MCF-7, respectively), compounds 20 , 21 , 22, 23, 24, 25, 26, and 28 exhibited superior cytotoxic activities with IC 50 values ranging from 1.78 to 9.19 µM. In order to sightsee the proposed mechanism of anti-proliferative activity, the most active members were further evaluated in vitro for their inhibitory activities against tubulin polymerisation. Compounds 21 and 32 exhibited the highest tubulin polymerisation inhibitory effect with IC 50 values of 9.11 and 10.5 nM, respectively. Such members showed activities higher than that of colchicine (IC 50  = 10.6 nM) and CA-4 (IC 50  = 13.2 nM). The impact of the most promising compound 25 on cell cycle distribution was assessed. The results revealed that compound 25 can arrest the cell cycle at G2/M phase. Annexin V and PI double staining assay was carried out to explore the apoptotic effect of the synthesised compounds. Compound 25 induced apoptotic effect on HepG-2 thirteen times more than the control cells. To examine the binding pattern of the target compounds against the tubulin heterodimers active site, molecular docking studies were carried out.

This work presents the design and synthesis of a series of new quinazolin-4-one derivatives, based on the established effectiveness of quinazoline-based small molecules as anticancer agents. Synthesized compounds were more potent against MCF-7 than A-549 with low to submicromolar IC 50 s. Compound 17 exhibited the best IC 50 being equipotent with the positive control doxorubicin (IC 50 = 0.06 μM) and better than 5-fluorouracil (IC 50 = 2.13 μM). Compound 17 was further tested against MDA-MB-231 and MCF-10A and was found to be > 2 folds more cytotoxic on MCF-7. Significant apoptotic activity was elicited by 17 on MCF-7 where it increased apoptotic cell death along with induction of pre-G1 and G1-phase cell cycle arrest. Similarly, 17 was able to induce apoptosis in MD-MB-231 treated cells associated with a disruption of the cell cycle causing arrest at the pre-G1 and S phases. Investigation of gene expression in MCF-7 demonstrated an increased expression of the proapoptotic genes P53, PUMA, Bax, caspases 3, 8 and 9 and a decrease of the anti-apoptotic gene Bcl2. Also, 17 reduced autophagy giving way for apoptosis to induce cancer cells death. This latter observation was associated with downregulation of EGFR and its downstream effectors PI3K, AKT and mTor. As its biomolecular target, 17 also inhibited EGFR similar to erlotinib (IC 50  = 0.072 and 0.087 μM, respectively). Additionally, in vivo testing in a mouse model of breast cancer affirmed the anti-tumor efficacy of 17. Finally, docking of 17 against EGFR ATP binding site demonstrated its ability to bind with EGFR resembling erlotinib., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

An efficient synthesis of substituted pyrido[2,3-d]pyrimidines was carried out and evaluated for in vitro anticancer activity against five cancer cell lines, namely hepatic cancer (HepG-2), prostate cancer (PC-3), colon cancer (HCT-116), breast cancer (MCF-7), and lung cancer (A-549) cell lines. Regarding HepG-2, PC-3, HCT-116 cancer cell lines, 7-(4-chlorophenyl)-2-(3-methyl-5-oxo-2,3-dihydro-1H-pyrazol-1-yl)-5-(p-tolyl)- pyrido[2,3-d]pyrimidin-4(3H)-one (5a) exhibited strong, more potent anticancer (IC 50 : 0.3, 6.6 and 7 µM) relative to the standard doxorubicin (IC 50 : 0.6, 6.8 and 12.8 µM), respectively. Kinase inhibitory assessment of 5a showed promising inhibitory activity against three kinases namely PDGFR β, EGFR, and CDK4/cyclin D1 at two concentrations 50 and 100 µM in single measurements. Further, a molecular docking study for compound 5a was performed to verify the binding mode towards the EGFR and CDK4/cyclin D1 kinases.

Objective and Background: Hydrazonoyl halides were used as precursors for the synthesis of a new series of bis-spiropyrazoles via reaction with 3,5-diarylidene-piperidone derivatives under ultrasound irradiation. The products were secluded in good yield after short reaction periods., Conclusion: The anticancer activity of bis-spiropyrazoles against HepG2 (hepatic cancer), A549 (lung cancer) and CaCo2 (colon cancer) cell lines was screened. Three tested compounds 4b, 4c and 4f showed promising activity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Structure-based pharmacophores were generated and validated using the bioactive conformations of different co-crystallized enzyme-inhibitor complexes for allosteric palm-1 and thumb-2 inhibitors of NS5B. Two pharmacophore models were obtained, one for palm-1 inhibitors with sensitivity = 0.929 and specificity = 0.983, and the other for thumb-2 inhibitors with sensitivity = 1 and specificity = 0.979. In addition, a quantitative structure activity relationship (QSAR) models were developed based on using the values of different scoring functions as descriptors predicting the activity on both allosteric binding sites (palm-1 and thumb-2). QSAR studies revealed good predictive and statistically significant two descriptor models (r 2  = .837, r 2 adjusted  = .792 and r 2 prediction  = .688 for palm-1 model and r 2  = .927, r 2 adjusted  = .908 and r 2 prediction  = .779 for thumb-2 model). External validation for the QSAR models assured their prediction power with r 2 ext  = .72 and .89 for palm-1 and thumb-2, respectively. Different docking protocols were examined for their validity to predict the correct binding poses of inhibitors inside their respective binding sites. Virtual screening was carried out on ZINC database using the generated pharmacophores, the selected valid docking algorithms and QSAR models to find compounds that could theoretically bind to both sites simultaneously.